6. journal.pgen.1001036

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PLoS Genetics | www.plo s genetics.org 1 July 2010 | Volume 6 | Issue 7 | e1001036

icroe!olution o" #elico$%cter pylori &uring Prolonge&In"ection o" Single #osts %n& wit'in (%milies

Gio!%nn% orelli1)%

* +%!ier ,i&elot2* -%ric% usece/

1)%* S%n&r% Sc'w%r0

3)$* 'ristelle -%'l%w%ne

3*

,%niel (%lus'* Se$%sti%n Suer$%um

3* %r/ c'tm%n

1*24

1 ,ep%rtment o" olecul%r -iology* %5Pl%nc/ Institute "or In"ection -iology* -erlin* Germ%ny* 2 ,ep%rtment o" St%tistics* ni!ersity o" 8%rwic/* 8%rwic/* nite&

ing&om* 3 Institute o" e&ic%l icro$iology %n& #ospit%l 9pi&emiology* #%nno!er e&ic%l Sc'ool* #%nno!er* Germ%ny* 9n!ironment%l :ese%rc' Institute %n&,ep%rtment o" icro$iology* ni!ersity ollege or/* or/* Irel%n&

$str%ct

;ur un&erst%n&ing o" $%sic e!olution%ry processes in $%cteri% is still !ery limite&. (or e5%mple* multiple recent &%tingestim%tes %re $%se& on % uni!ers%l interspecies molecul%r cloc/ r%te* $ut t'%t r%te w%s c%li$r%te& using estim%tes o"geologic%l &%tes t'%t %re no longer %ccepte&. 8e t'ere"ore estim%te& t'e s'ortterm r%tes o" mut%tion %n& recom$in%tionin #elico$%cterpylori$y se70 "romt'e Si5t' :ese%rc' (r%mewor/ Progr%mme o" t'e 9urope%n nion %n& 9:6H9? P%t'oGenoics #9L,IVH9? to SS* %n& 0@E(91E->>2 AScience (oun&%tion o"Irel%n&C to . ?'e "un&ers '%& no role in stu&y &esign* &%t% collection %n& %n%lysis* &ecision to pu$lis'* or prep%r%tion o" t'e m%nuscript.

ompeting InterestsB ?'e %ut'ors '%!e &ecl%re& t'%t no competing interestse5ist.

4 96m%ilB m.%c't m%nucc.ie

)% urrent %&&ressB %5Pl%nc/ Institute "or olecul%r Genetics* -erlin* Germ%ny)$ urrent %&&ressB,ep%rtment o" icro$iology* ni!ersity o" 8%s'ington* Se%ttle* 8%s'ington* nite& St%tes o" meric%

Intro&uction

8'en &i& mo&ern p%t'ogenic $%cteri% e!ol!e urrent wis&om

te%c'es t'%t 10*000D@0*000 ye%rs '%!e el%pse& since % !%riety o"genetic%lly 'ig'ly monomorp'ic $%cteri%l p%t'ogens e!ol!e& "romt'eir l%st common %ncestors K1D6 %n& t'e %ges o" p%t'ogenic

$%cteri% wit' gre%ter le!els o" genetic &i!ersity '%!e $een

estim%te& %s re"lecting millions o" ye%rs o" e!olution K7*>. ge

estim%tes "or $%cteri% %re 'ig'er t'%n t'ose o" !iruses* m%ny o"

w'ic' %ppe%re& % "ew 'un&re& ye%rs %go K=* prim%rily $ec%use

m%ny $%cteri%l estim%tes %re $%se& on % suppose&ly uni!ers%l

molecul%r cloc/ r%te* mS*"or synonymouspolymorp'isms in genes

t'%t enco&e proteins. In 1=>7* ;c'm%n %n& 8ilson c%li$r%te& t'iscloc/ r%te %s 3.610

2=per nucleoti&e per ye%r $y &%ting t'e

split $etween 9sc'eric'i% coli %n& S%lmonell% enteric% wit'in t'e

"r%mewor/ o" % uni!ers%l cloc/ r%te "or $%cteri%l r:H

se

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ut%tion %n& :ecom$in%tion :%tes in #. pylori

ut'or Summ%ry

ut%tion r%tes in $%cteri% '%!e gener%lly $een consi&ere&to $e muc' slower t'%n in !iruses. ?'is is p%rtly $ec%useestim%tes o" longterm mut%tion r%tes "or t'e e!olution o"&istinct species '%!e $een in%ppropri%tely use& "or &%ting&i!ergence wit'in species. (urt'ermore* t'e most commonly use& longterm mut%tion r%te is $%se& ongeologic%l &%tes t'%t %re no longer %ccepte&. In %&&ition*only "ew s'ortterm mut%tion r%tes '%!e $een c%lcul%te&

wit'in $%cteri%l species* %n& t'ese &i""er wit' t'e species$y se!er%l or&ers o" m%gnitu&e. #ere* we pro!i&e ro$ustestim%tes "or s'ortterm mut%tion %n& recom$in%tion r%teswit'in #elico$%cter pylori* % $%cterium t'%t commonlyin"ects t'e 'um%n g%stric mucos%* $%se& on seri%l isol%tes"rom longterm in"ections %n& on &i""erences $etweenisol%tes "rom multiple "%mily mem$ers. ?'ese s'orttermmut%tion r%tes %re @D17"ol& "%ster t'%n longtermmut%tion r%tes in #. pylori t'%t '%!e $een c%li$r%te& $y

p%r%llel %ncient migr%tions o" 'um%ns. S'ortterm mut%tion r%tes in $%cteri%* inclu&ing t'ose "or #.pylori* c%n $e7 K10 wit' current estim%tes.

?ime Point 9!ent ;l& 9stim%te AM%C urrent 9stim%teAM%C it%tion

y%no$%cteri% .1*300 .2*00 K6

- P'otosynt'etic eu/%ryotes

.

>00

.

1*200 K6@ ;5ygen

*

2*000 2*300 K66

, ;5i&%ti!eeu/%ryotes .>00 .1*00 K67

9 #ig' concentr%tion ;2 *>00

( Lig't org%ns .@0

G 9yes *@00 .@31 K6>

# L%n& pl%nts *00 @0

I %mm%ls *1@0 .162 K6=

J Legumes .100 .> K70

&oiB10.1371EFourn%l.pgen.1001036.t001

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(igure 1. Percent%ge &i!ersity in r:H !ersus %ge Amillion ye%rsC. AC origin%l correl%tion $y ;c'm%n %n& 8ilson K10. A-C l%c/ o" goo&correl%tion %ccor&ing to mo&ern estim%tes o" %ge r%nges A?%$le 1C.&oiB10.1371EFourn%l.pgen.1001036.g001

r%te. In&ee&* t'e "re ye%rsC.Ho se

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?%$le 2. Pu$lis'e& %ges %n& cloc/ r%tes "or microe!olution in selecte& $%cteri%.

?%5on loc/ r%te ge AyrsC it%tion S%mpling perio& AyrsC

%mpylo$%cter FeFuni mSO 2.>6102@

00 K20 3

p%n&emic Vi$rio c'oler%e mSO 6.76102@

130 K21 3

St%p'ylococcus %ureus S?23= m O 3.361026

@ K22 21

Mersini%pestis A%&%g%sc%rC m O >.66

10

2=

100 su$mitte& 70#. pylori seri%l isol%tes mSO

*

26102@

.

11*000 K= 1.>

-uc'ner% AHort' meric%C mSO 2.261027

*13@ K71 e5t%nt

#. pylori in P%ci"ic m O 2.661027

70*000 K2= e5t%nt

H;?9B #. pylori in P%ci"ic w%s c%lcul%te& "rom t'e r%w output o" t'e lon%l(r%me %n%lyses in cit%tion K2= %s m O t'et%E2Eco%lescent unitEconc%ten%te& se A=@ con"i&ence inter!%l KI @0>.D=>@.=C* co%lescent unit w%s 00*000 yrs %n& conc%ten%te& se610

27to 3.6610

27.

mSB synonymous cloc/ r%te per nucleoti&e per ye%r.

mB mut%tion%l cloc/ r%te per nucleoti&e per ye%r. ?'e s%mpling perio& is &esign%te& %s e5t%nt w'en &%te o" s%mpling w%s not consi&ere& in &%te estim%tes.&oiB10.1371EFourn%l.pgen.1001036.t002

t'ree p%irs o" isol%tes &i""ere& $y % single nucleoti&e* %n& si5 p%irs

o" isol%tes &i""ere& $y eig't mos%ic stretc'es. A(our ot'er p%irs

were e5clu&e& "rom %n%lysis $ec%use t'ey eit'er re"lecte& mi5e&

in"ections wit' genetic%lly unrel%te& str%ins or %n in"ection wit'

% clou& o" rel%te& isol%tes w'ose genetic &i!ersity '%& %risenprior

to in"ection.C (or t'e 6 p%irs o" isol%tes wit' mos%ic stretc'es*

'omologous recom$in%tion '%& intro&uce& imports o" %n %!er%ge

sie o" 17 $p AI K=@ con"i&ence inter!%l 2@=D732C %t % r%teper nucleoti&e per ye%r o" 6.=610

2@AI 3.@610

2@to

1.26102

C.

?'e t'ree p%irs t'%t &i""ere& $y % single polymorp'ism were use&

to c%lcul%te % m%5im%l mut%tion r%te per nucleoti&e per ye%r o".1610

2@* $ut t'ese polymorp'isms coul& not $e

&e"initi!ely

%scri$e& to mut%tion $ec%use t'ey mig't '%!e represente&

%typic%lly s'ort imports K=.

#ere we '%!e re%n%lye& t'e s%me p%irs o" isol%tes plus ot'ers

t'%t sp%nne& longer time perio&s. 8e e5%mine& t'e se gene "r%gments in or&er to pro!i&e ro$ust s'ort

term cloc/ r%tes "or mut%tion %n& recom$in%tion. ?'ese cloc/r%tes were comp%re& to longterm cloc/ r%tes t'%t were c%li$r%te&

$y t'e &%tes o" 'um%n migr%tions.

:esults

Ho!el nucleoti&e se gene "r%gments "rom se!en genomic seC


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(igure 2. Se3 s'owe& one nucleoti&e &i""er

ence* 30 '%& two %n& 1>6 '%& %t le%st t'ree. #owe!er* %lt'oug'

t'e longer time sp%n "or &i!ergence o" t'e "%mily isol%tes w%s

e5pecte& to s'ow e!en stronger correl%tions wit' time* t'is w%s

not t'e c%se. Inste%&* we coul& not "in& % signi"ic%nt

correl%tion $etween t'e num$ers o" noni&entic%l gene"r%gments %n& %ny "unction o" t'e %ge o" t'e "%mily mem$ers

t'%t w%s teste&. (or e5%mple* i" in"ection were tr%nsmitte& to

si$lings or c'il&ren w'en t'ey re%c'e& 20 ye%rs o" %ge* %

signi"ic%nt correl%tion s'oul& '%!e $een o$ser!e& $etween t'e

num$ers o" &istinct gene "r%gment se6 (igure 3,C. Visu%l e5%min%tion o"

t'e &%t% in&ic%te& t'%t t'is l%c/ o" correl%tion wit' %ge l%rgely

re"lecte& two "%milies* num$ers 23 %n& 26* w'ic' '%& unusu%lly

'ig' le!els o" polymorp'ism. "ter remo!%l o" &%t% "rom t'ese

two "%milies* t'e num$er o" &i""erences w%s signi"ic%ntly

correl%te& wit' m%5im%l %ge A: O 0. p O 0.0@ (igure S1,C.

o&el$%se& %n%lysis8e &esigne& % st%tistic%l mo&el o" t'e microe!olution%ry

process in or&er to %n%lye our &%t%. ;ur mo&el %ssumes t'%t

e%c' se

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(igure 3. ge !ersus num$er o" &i""erent gene "r%gments in p%irwise comp%risons. A*-C seri%l isol%tes. A* ,C isol%tes wit'in e%c' "%mily.AC inimum %ge w%s t'e time sep%r%tion $etweenp%irs o" isol%tes. A-C %5imum %ge w%s t'e sum o" t'e %ges o" t'e in"ecte& person upon isol%tiono" t'e seri%l isol%tes. AC inimum %ge w%s t'e minimum %ge o" t'e two su$FectsQ20. A,C %5imum %ge w%s t'e sum o" t'e %ges o" t'e two "%milymem$ers. 9%c' plot cont%ins % line%r regression o" t'e &%t%* w'ose correl%tion A:C %n& pro$%$ility ApC %re in&ic%te& %$o!e t'e plot.&oiB10.1371EFourn%l.pgen.1001036.g003

in"ecte& w'om. ?'ere"ore* we m%&e no %ssumptions %$out

p'ylogeny $ut r%t'er per"orme& p%irwise comp%risons o" e%c'

p%ir o" isol%tes wit'in % "%mily. ?'is tec'ni

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(igure . P%irwise comp%rison o" se11721 1*1= K100>1763

n Apolymorp'ism r%teC 0.016 K0.0060.026 0.022 K0.0170.02>

n J l Apolymorp'ismsC 1>.62 K7.672>.03 30.=6 K20.=16.13

rEm 0.1= K0.110.26 0.1> K0.130.2@

r J l J nEm 3.3@ K1.66@.@6 @.= K3.6>.06


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(igure @. omp%risons o" o$ser!e& %n& simul%te& &%t% "or se

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9/13

?'e r%tio rEm s'oul& $e % ro$ust me%sure o" t'e rel%ti!e"re*!ery simil%r to t'e estim%te o" 0.1= "or t'e seri%l isol%tes A?%$le C.Simil%rly* t'e tr%ct lengt' l %n& t'e "reD@2 times t'e r%te in M.pestis A?%$le 2C. ?'ese comp%risons s'ow t'%t t'e s'ortterm cloc/r%te !%ries &r%m%tic%lly %mong &i""erent $%cteri%* %n& in somec%ses o!erl%ps wit' t'ose o" :H !iruses K60. #owe!er* in %llc%ses consi&ere& 'ere* it is 'ig'er t'%n t'e longterm AsynonymousCcloc/ r%te o" 3.610

2=t'%t '%s o"ten $een use& until now to

c%lcul%te t'e %ges o" genetic%lly monomorp'ic $%cteri%.

%teri%ls %n& et'o&s

-%cteri%l isol%tes8e stu&ie& two types o" $%cteri%l isol%tes o" #. pyloriB seri%l

isol%tes w'ic' were collecte& "rom in&i!i&u%l persons %"ter %

speci"ie& time inter!%l* %n& "%mily isol%tes w'ic' were collecte&concurrently "rom two or more mem$ers o" t'e s%me "%mily A?%$leS2C. ?'e 6> seri%l isol%tes were collecte& "rom 3 p%tients %t

inter!%ls r%nging "rom 3 mont's to 10.2 ye%rs. ?'e 2= "%mily

isol%tes were collecte& "rom 2 to @ mem$ers o" 10 "%milies.

Hucleoti&e se

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pro&ucts were cle%ne& $y using s'rimp %l/%line p'osp'%t%se plus

e5onucle%se I. ll se gene "r%gments w'ose se gene "r%gments "rom genomic

se

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:e"erences

1. c'tm%n * orelli G* R'u P* 8irt' ?* ,ie'l I* et %l. A200C icroe!olution%n& 'istory o" t'e pl%gue $%cillus* Mersini% pestis. Proc H%tl c%& Sci ASC101B17>37D17>2.

2. :oum%gn%c P* 8eill (+* ,olece/ * -%/er S* -risse S* et %l. A2006C9!olution%ry 'istory o" S%lmonell% ?yp'i. Science 31B 1301D130.

3. Hu $el * :oum%gn%c P* (el&/%mp * Song J#* o S* et %l. A200>C(re6=D=>7.@. Pupo G* L%n :* :ee!es P: A2000C ultiple in&epen&ent origins o" S'igell%

clones o" 9sc'eric'i% coli %n& con!ergent e!olution o" m%ny o" t'eirc'%r%cteristics. Proc H%tl c%& Sci AS C =7B 10@67D10@72.

6. Leopol& S:* %grini V* #olt HJ* S'%i/' H* %r&is 9:* et %l. A200=C precisereconstruction o" t'e emergence %n& constr%ine& r%&i%tions o" 9sc'eric'i% coli;1@7 portr%ye& $y $%c/$one conc%tenomic %n%lysis. Proc H%tl c%& Sci ASC106B >713D>71>.

7. P%r/'ill J* Se$%i'i% * Preston * urp'y L,* ?'omson H* et %l. A2003Comp%r%ti!e %n%lysis o" t'e genome se6.

11. S'eri&%n PP* (reem%n #* -renc'ley J9 A2003C9stim%te& minim%l &i!ergencetimes o" t'e m%For $%cteri%l %n& %rc'%e%l p'yl%. Geomicro$iology Journ%l 20B1D1.

12. 8irt' ?* (%lus' ,* L%n :* olles (* ens% P* et %l. A2006C Se5 %n& !irulence in9sc'eric'i% coliB %n e!olution%ry perspecti!e. ol icro$iol 60B 1136D11@1.

13. -%ttistui (* (eiF%o * #e&ges S- A200C genomic timesc%le o" pro/%ryotee!olutionB insig'ts into t'e origin o" met'%nogenesis* p'ototrop'y* %n& t'ecoloni%tion o" l%n&. - 9!ol -iol B .

1. #o SM* L%rson G A2006C olecul%r cloc/sB w'en times %re %c'%nginN. ?ren&sGenet 22B 7=D>3.

1@. #o SM* S'%piro -* P'illips J* ooper * ,rummon& J A2007C 9!i&ence "ortime &epen&ency o" molecul%r r%te estim%tes. Syst -iol @6B @1@D@22.

16. :oc'% 9P* Smit' J* #urst L,* #ol&en ?* ooper J9* et %l. A2006Comp%risons o" &HE&S %re time &epen&ent "or closely rel%te& $%cteri%lgenomes. J t'eor -iol 23=B 226D23@.

17. ry%'ims/iy S* Plot/in J- A200>C ?'e popul%tion genetics o" &HE&S. PLoSGenet B e100030. &oiB10.1371EFourn%l.pgen.100030.

1>. ;c'm%n #* 9lwyn S* or%n H A1===C %li$r%ting $%cteri%l e!olution. ProcH%tl c%& Sci AS C =6B 1263>D1263.

1=. c'tm%n A200>C 9!olution* popul%tion structure %n& p'ylogeogr%p'y o"

genetic%lly monomorp'ic $%cteri%l p%t'ogens. nnu :e! icro$iol 62B @3D70.

20. 8ilson ,J* G%$riel 9* Le%t'er$%rrow J* 'ees$roug' J* Gee S* et %l. A200=C:%pi& e!olution %n& t'e import%nce o" recom$in%tion to t'e g%stroenteric

p%t'ogen %mpylo$%cter FeFuni. ol -iol 9!ol 26B 3>@D3=7.

21. (eng L* :ee!es P:* L%n :* :en M* G%o * et %l. A200>C rec%li$r%te& molecul%rcloc/ %n& in&epen&ent origins "or t'e c'oler% p%n&emic clones. PLoS ;H9 3B

e0@3. &oiB10.1371EFourn%l.pone.0000@3.

22. #%rris S:* (eil 9J* #ol&en ?* Tu%il * Hic/erson 9* et %l. A2010C9!olution o" :S &uring 'ospit%l tr%nsmission %n& intercontinent%l spre%&.Science 327B 6=D7.

23. en% * Smit' 99* -urns JL* Speert ,P* os/owit S* et %l. A200>C Genetic%&%pt%tion o" Pseu&omon%s %eruginos% to t'e %irw%ys o" cystic "i$rosis p%tients isc%t%lye& $y 'ypermut%tion. J -%cterio l 1=0B 7=10D7=17.

2. Smit' 99* -uc/ley ,G* 8u R* S%enp'imm%c'%/ * #o""m%n L:* et %l. A2006CGenetic %&%pt%tion $y Pseu&omon%s %eruginos% to t'e %irw%ys o" cystic "i$rosis

p%tients. Proc H%tl c%& Sci ASC103B >>7D>=2.

2@. w%ngi * 8u S8* R'ou M* Sier%&/i * ,e Lenc%stre #* et %l. A2007C?r%c/ing t'e in !i!o e!olution o" multi&rug resist%nce in St%p'ylococcus %ureus $yw'olegenome seD3@@@.27. '%ttop%&'y%y S* 8eissm%n SJ* inin VH* :usso ?* ,y/'uien ,9* et %l.

A200=C#ig' "reB 1607D1612.

36. %ng J* Io!ine H* -l%ser J A2006C p%r%&igm "or &irect stressin&uce&

mut%tion in pro/%ryotes. (S9- J 20B 276D2>@.

37. Lin R* Hei * % # A2007C ?'e origins %n& e%rly e!olution o" ,H mism%tc'rep%ir genesDmultiple 'oriont%l gene tr%ns"ers %n& coe!olution. Hucleic ci&s:es 3@B 7@=1D7603.

3>. %ng J* -l%ser J A2006C -%cteri%l popul%tions %s per"ect g%sesB genomic

integrity %n& &i!ersi"ic%tion tensions in #elico$%cter pylori. H%t :e! icro$iol B>26D>36.

3=. Suer$%um S* %yn%r& Smit' J* -%pumi% * orelli G* Smit' H#* et %l. A1==>C(ree recom$in%tion wit'in #elico$%cter pylori. Proc H%tl c%& Sci A S C =@B1261=D1262.

0. einersm%nn :J* :omeroG%llo J* -l%ser J A200>C:%te 'eterogeneity in t'ee!olution o" #elico$%cter pylori %n& t'e $e'%!ior o" 'omopl%stic sites. In"ect Genet9!ol >B @=3D602.

1. ulic/ S* occi% * ,i&elot +* (%lus' ,* r%"t * et %l. A200>C os%ic ,Himports wit' interspersions o" recipient seD=23.

. -erg ,9* Gilm%n :#* Lelw%l%Guruge J* Sri!%st%!% * V%l&e M* et %l. A1==7C#elico$%cter pyloripopul%tions in Peru!i%n p%tients. lin In"ect ,is 2@B ==6D1002.

@. ersulyte ,* '%l/%us/%s #* -erg ,9 A1===C 9mergence o" recom$in%nt str%inso" #elico$%cter pylori &uring 'um%n in"ection. ol icro$iol 31B 31D3.

6. :%ymon& J* ?'i$erg J* 'e!%lier * %l%c' H* -ergeret * et %l. A200CGenetic %n& tr%nsmission %n%lysis o" #elico$%cter pylori str%ins wit'in % "%mily.9merg In"ect ,is 10B 1>16D1>21.

7. Sc'w%r S* orelli G* usece/ -* %nic% * -%llou5 (* et %l. A200>C #oriont%l!ersus "%mili%l tr%nsmission o" #elico$%cter pylori. PLoS P%t'og B e10001>0.&oiB10.1371EFourn%l.pp%t.10001>0.

>. ?%l%rico S* Gol& -,* (ero J* ?'ompson ,?* Gu%rner J* et %l. A200=C Pe&i%tric

#elico$%cter pylori isol%tes &ispl%y &istinct gene co&ing c%p%cities %n& !irulencegene m%r/er pro"iles. J lin icro$iol 7B 16>0D16>>.

=. (%lus' ,* r%"t * ?%ylor HS* orre% P* (o5 JG* et %l. A2001C :ecom$in%tion%n& mut%tion &uring longterm g%stric coloni%tion $y #elico$%cter pyloriB9stim%tes o" cloc/ r%tes* recom$in%tion sie %n& minim%l %ge. Proc H%tl c%&

Sci AS C =>B 1@0@6D1@061.@0. uipers 9J* Isr%el ,* usters JG* Gerrits * 8eel J* et %l. A2000C

Tu%sispecies &e!elopment o" #elico$%cter pylori o$ser!e& in p%ire& isol%teso$t%ine& ye%rs %p%rt "rom t'e s%me 'ost. J In"ect ,is 1>1B 273D2>2.

@1. ,i&elot +* (%lus' , A2007C In"erence o" $%cteri%l microe!olution usingmultilocus se.

@. ?%!%re S* %rs'%ll :* 8ill ;* Soligo * %rtin :, A2002C sing t'e "ossil

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60. #olmes 9 A2010C ?'e comp%r%ti!e genomics o" !ir%l emergence. Proc H%tlc%& Sci ASC107 Supplement 1B 172D176.

61. Jolley * '%n S* %i&en A200C mlst&$Het &istri$ute& multilocus se11D3>26.

67. J%!%u5 9J* noll #* 8%lter : A2001C orp'ologic%l %n& ecologic%l

comple5ity in e%rly eu/%ryotic ecosystems. H%ture 12B 66D6=.

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210=3.

71. or%n H* cL%ug'lin #J* Sore/ : A200=C ?'e &yn%mics %n& time sc%le o"

ongoing genomic erosion in sym$iotic $%cteri%. Science 323B 37=D3>2.

i/roe!olusi #elico$%cter pylori sel%m% In"e/si

$er/ep%nF%ng%n #ost Single &%n &%l%m elu%rg%
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pem%'%m%n /it% tent%ng proses e!olusi &%s%r &%l%m

$%/teri m%si' s%ng%t ter$%t%s. is%lny%* $e$er%p%

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memper/ir%/%n su/u $ung% F%ng/% pen&e/ mut%si &%n

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ini term%su/

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ting/%t mut%si* re/om$in%si* $er%rti p%nF%ng s%lur%n

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y%ng tig% /%li le$i' $%ny%/ su$stitusi y%ng

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peng'%pus%n mut%si noni&enti/ /%ren% sele/si pemurni.

Per$%n&ing%n &eng%n liter%tur ter$%ru menunFu//%n

$%'w% ting/%t mut%si F%ng/% pen&e/ $er!%ri%si sec%r%

&r%m%tis &%l%m spesies $%/teri y%ng $er$e&% &%n &%p%t

sp%n $er$%g%i $e$er%p% /%li lip%t.

6. journal.pgen.1001036

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